This project, entitled "New Strategies to Prevent Death from Influenza" is designed to respond to the imminent introduction of new strains of influenza virus into the population, either through a natural pandemic or via bioterrorism. Two strategies are described;one to treat the Acute Respiratory Distress Syndrome (ARDS) by blocking immunopathology after infection, and secondly, to prevent/attenuate the ARDS by new approaches to develop "T cell vaccines and adjuvants." In the first aim, we plan to extend on our data, which already indicate that anti-TNF agents can prevent the ARDS, by determining how long after infection TNF can still be effective, by testing new short-acting truncated TNF receptors (TRUCEPT), by blocking the cells that are responsible for producing TNF and other proinflammatory cytokines via recombinant proteins that block the costimulatory T cell molecule OX40, and by activating an inhibitory molecule, CD200R, on antigen presenting cells (APC). In the second aim we plan to extend experimental data, which indicate that vaccination with live influenza viruses can markedly attenuate morbidity and mortality to a lethal exposure to a virus strain that does not share antibody cross-reacting antigens. Subsequently, we plan to compare immunity raised using live viruses with safe, non-replicating Adenovirus vaccine vectors that contain influenza genes in addition to an adjuvant gene that activates NF-kB, thereby upregulating APC function. To ensure maximal immunization of T cells, two approaches will be tested to boost the number and function of responding T cells: interleukin-2 (IL2) and OX40L-lg. Thus, the strategy is to use a dual approach to the development of safe vaccines that can be used to immunize the world's population, including those individuals most at risk, the very young, the elderly, and the immunocompromised. This is a collaborative effort between two established research teams, one in New York City, and one in London, UK with complementary skills and whose members know each other well. The experiments are focused on preclinical animal models, but are designed to build toward relevant clinical problems. If successful, this research effort will provide the foundation for the development of a universal approach to the prevention and treatment of one of the world's most dangerous microbes, one that kills hundreds of thousands yearly.